# US 2013/0158081 A1 · Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid

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- Number: US 2013/0158081 A1
- Document ID: US20130158081A1
- Status: Published application
- Kind: A1
- Application number: 13/764,807
- Filed: 2013-02-12
- Published: 2013-06-20
- Earliest claimed: 2006-09-25
- Assignees: PTC Therapeutics, Inc.
- Inventors: Neil G. Almstead; Peter Seongwoo Hwang; Young-Choon Moon
- Web page: https://patentgrep.com/patent/US20130158081A1

## CPC

- A61K 31/4245: Oxadiazoles
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, pharmaceutical compositions and dosage forms comprising the crystalline forms, methods of making the crystalline forms and methods for their use for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay.

## Claims

### Claim 1

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form A crystals characterized by at least one of the following:
(a) unit cell parameters when measured at 150 K: a=24,220 Å; b=3,74640 Å; c=27,4678 Å; α=90°; β=92,9938°; γ=90°; V=2489,38(17) Å3; Z=8; calculated density (dcalc, g cm−3) is 1,517 g cm−3; and the space group is P21/n (no. 14);
(b) an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2), when measured using Cu Kα radiation, selected from the group consisting of:
4.96
6.39
10.10
11.54
12.62
12.81
13.92
14.16
14.55
14.88
15.07
15.58
16.27
16.61
18.74
18.94
19.28
19.94
20.27
20.74
20.97
21.22
21.93
22.58
22.80
23.00
23.79
24.14
24.46
25.44
25.64
26.07
26.34
26.74
27.06
27.79
28.42
29.09
30.48
(c) a thermogravimetric analysis thermogram which has a mass loss of less than 1% of the total mass of the sample upon heating from 33° C. to 205° C.;
(d) a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 244° C.; and
(e) fractional atomic coordinates equal to the following coordinates:
Átom
x
y
z
U(Å2)
F(122)
0.43198(12)
0.7655(8)
−0.17546(10)
0.0487(10)
F(222)
−0.20343(15)
0.7129(10)
0.06378(14)
0.0781(14)
O(13)
0.42977(13)
0.4875(8)
−0.08927(11)
0.0324(10)
O(23)
−0.12941(13)
0.4507(9)
0.12653(12)
0.0402(10)
O(151)
0.25519(13)
0.4795(9)
0.10765(12)
0.0382(10)
O(152)
0.29215(13)
0.2155(9)
0.17515(12)
0.0403(10)
O(251)
0.16226(13)
0.4813(9)
0.15012(12)
0.0385(10)
O(252)
0.19645(13)
0.1939(9)
0.21659(12)
0.0393(10)
N(11)
0.35817(15)
0.5856(9)
−0.04386(14)
0.0279(10)
N(14)
0.44373(16)
0.3409(10)
−0.04263(14)
0.0327(12)
N(21)
−0.04134(16)
0.5165(9)
0.11065(14)
0.0305(12)
N(24)
−0.09772(17)
0.3201(11)
0.16787(15)
0.0388(14)
C(12)
0.37827(18)
0.6256(11)
−0.08637(17)
0.0266(14)
C(15)
0.40019(19)
0.4091(11)
−0.01823(17)
0.0261(14)
C(22)
−0.0926(2)
0.5601(12)
0.09502(18)
0.0319(15)
C(25)
−0.0471(2)
0.3690(11)
0.15580(17)
0.0302(15)
C(121)
0.35225(19)
0.7961(11)
−0.12930(17)
0.0291(14)
C(122)
0.3784(2)
0.8567(12)
−0.17244(18)
0.0345(15)
C(123)
0.3519(2)
1.0117(12)
−0.21257(19)
0.0407(17)
C(124)
0.2973(2)
1.1101(13)
−0.21014(19)
0.0416(17)
C(125)
0.2694(2)
1.0543(12)
−0.1677(2)
0.0409(17)
C(126)
0.2966(2)
0.8996(12)
−0.12784(18)
0.0349(15)
C(151)
0.39702(19)
0.3013(11)
0.03319(16)
0.0260(14)
C(152)
0.34897(19)
0.3623(11)
0.05704(16)
0.0261(15)
C(153)
0.34631(18)
0.2594(11)
0.10554(16)
0.0253(14)
C(154)
0.39150(19)
0.0970(11)
0.13029(17)
0.0279(14)
C(155)
0.43977(19)
0.0412(11)
0.10614(17)
0.0291(15)
C(156)
0.44250(19)
0.1421(11)
0.05765(17)
0.0292(15)
C(157)
0.2955(2)
0.3188(12)
0.13209(18)
0.0312(15)
C(221)
−0.1109(2)
0.7083(12)
0.04727(19)
0.0388(17)
C(222)
−0.1643(3)
0.7823(15)
0.0331(2)
0.053(2)
C(223)
−0.1825(3)
0.9272(15)
−0.0122(3)
0.064(2)
C(224)
−0.1415(4)
0.9930(16)
−0.0433(3)
0.068(3)
C(225)
−0.0870(3)
0.9202(15)
−0.0316(2)
0.066(2)
C(226)
−0.0678(3)
0.7766(12)
0.01365(17)
0.0543(19)
C(251)
0.00110(19)
0.2695(11)
0.18877(17)
0.0300(15)
C(252)
0.05426(19)
0.3352(11)
0.17481(17)
0.0289(15)
C(253)
0.09949(19)
0.2449(11)
0.20524(17)
0.0277(15)
C(254)
0.0919(2)
0.0940(11)
0.25087(17)
0.0296(15)
C(255)
0.0389(2)
0.0335(11)
0.26491(17)
0.0300(15)
C(256)
−0.0064(2)
0.1185(12)
0.23430(17)
0.0322(15)
C(257)
0.1559(2)
0.3165(12)
0.18902(17)
0.0305(15)
H(123)
0.371
1.050
−0.241
0.048
H(124)
0.278
1.217
−0.238
0.050
H(125)
0.232
1.123
−0.166
0.049
H(126)
0.278
0.862
−0.099
0.042
H(151)
0.227
0.491
0.125
0.057
H(152)
0.318
0.473
0.041
0.031
H(154)
0.389
0.025
0.163
0.033
H(155)
0.471
−0.066
0.123
0.035
H(156)
0.475
0.103
0.041
0.035
H(223)
−0.220
0.975
−0.020
0.077
H(224)
−0.151
1.094
−0.074
0.082
H(225)
−0.061
0.969
−0.055
0.080
H(226)
−0.030
0.729
0.021
0.065
H(252)
0.226
0.213
0.202
0.059
H(254)
0.123
0.034
0.272
0.035
H(255)
0.033
−0.068
0.296
0.036
H(256)
−0.043
0.074
0.244
0.039
H(25A)
0.060
0.443
0.144
0.035
wherein the process comprises:
(1) crystallizing Form A from a solvent; or
(2) exposing a Form B crystal to a relative humidity of 79% at 60° C.; or
(3) milling a Form B crystal at ambient or sub-ambient temperature; or
(4) slurrying a Form B crystal in methyl isobutyl ketone, or a 1:1 mixture of dioxane and water; or
(5) subliming or heating a Form B crystal.

### Claim 2 (depends on 1)

The process of claim 1, wherein crystallizing Form A from a solvent comprises:
(a) crystallizing Form A from methanol, t-butanol, 1-butanol, acetonitrile, isopropyl alcohol (IPA), isopropyl ether, dimethyl formamide, heptane, isopropyl acetate, toluene or water;
(b) crystallizing Form A by slow evaporation from acetonitrile; t-butanol; isopropyl alcohol; or isopropyl ether; or
(c) crystallizing Form A by fast evaporation from 1-butanol; dimethoxyether; t-butanol; a mixture of dimethyl formamide and water; isopropyl ether; or a mixture of t-butanol:water (in a 3:2 ratio), 1 molar equivalent methanol and 1 molar equivalent sodium chloride.

### Claim 3 (depends on 1)

The crystal form produced by the process of claim 1, wherein said crystal form is physically stable: (1) when stored for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C.; 75% relative humidity at 40° C.; 50% relative humidity at 60° C. or 79% relative humidity at 60° C., (2) when milled at ambient and at sub-ambient temperatures, or (3) when slurried at one or more of the following conditions: in 1-BuOH for four days at ambient temperature, in chloroform for two days at 50° C. or in dichloromethane for two days at 50° C.

### Claim 4 (depends on 2)

The crystal form produced by the process of claim 2, wherein said crystal form is physically stable: (1) when stored for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C.; 75% relative humidity at 40° C.; 50% relative humidity at 60° C. or 79% relative humidity at 60° C., (2) when milled at ambient and at sub-ambient temperatures, or (3) when slurried at one or more of the following conditions: in 1-BuOH for four days at ambient temperature, in chloroform for two days at 50° C. or in dichloromethane for two days at 50° C.

### Claim 4

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by at least one of the following:
(a) an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2), when measured using Cu Kα radiation, selected from the group consisting of:
6.14
6.39
6.96
7.92
10.78
12.44
12.61
12.88
13.52
13.78
13.97
14.30
15.46
15.68
15.89
16.33
16.76
17.03
20.10
21.03
23.34
23.86
24.18
24.42
24.64
26.62
26.96
27.29
27.64
27.96
28.81
31.05
32.38
32.58
36.23
37.81
38.28
38.44
39.16
(b) a thermogravimetric analysis thermogram which has a mass loss of less than 5% of the total mass of the sample upon heating from 25° C. to 165° C.; and
(c) a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 243° C.,
wherein the process comprises heating Form A in 1-propanol.

### Claim 6 (depends on 5)

The crystal form produced by the process of claim 5, wherein said crystal form is physically stable: (1) upon storage for six days at one or more of the following relative humidity conditions: 53% relative humidity at 40° C., 75% relative humidity at 40° C. or 50% relative humidity at 60° C., (2) when under compression alone, (3) when under compression in the presence of a 1:1 mixture of t-BuOH and water, or (4) when slurried for 1 day at ambient temperature in THF:heptane (1:1).

### Claim 7

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 1), when measured using Cu Kα radiation, selected from the group consisting of:
6.42
7.00
7.89
10.85
12.61
12.92
13.47
13.97
15.81
16.45
17.12
20.05
21.05
23.92
24.28
27.00
27.39
27.84
28.04
28.94
31.10
32.58
36.11
37.71
38.15
38.61
wherein the process comprises slurrying Form A in 1-butyl acetate.

### Claim 8

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 2), when measured using Cu Kα radiation, selected from the group consisting of:
6.10
6.38
6.54
7.10
8.02
10.91
12.71
13.50
13.62
13.86
14.10
15.56
15.70
15.91
16.55
16.96
17.22
17.50
19.82
20.08
20.34
21.15
23.78
23.93
24.38
24.56
26.88
27.16
27.48
27.88
28.04
28.78
29.02
32.71
36.01
38.10
38.56
39.38
wherein the process comprises slurrying a mixture of the crystal form and Form A in a 1:1 mixture of tetrahydrofuran:heptanes with heating.

### Claim 9

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 3), when measured using Cu Kα radiation, selected from the group consisting of:
1.79
2.30
2.57
2.78
3.29
3.59
3.89
4.07
4.34
4.49
4.76
5.06
6.47
6.91
7.96
10.89
12.87
13.58
13.99
15.97
16.48
17.10
20.00
20.36
21.04
23.40
24.29
24.89
26.87
27.49
27.80
28.07
29.08
38.61
wherein the process comprises storing the crystal form in 75% relative humidity at 40° C.

### Claim 10

A process for preparing a crystal form of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid comprising Form B crystals characterized by an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) (shifted 3), when measured using Cu Kα radiation, selected from the group consisting of:
6.22
6.51
7.13
8.17
10.91
12.87
13.80
14.12
14.28
15.78
16.23
16.54
17.15
20.33
21.22
21.36
23.94
24.30
27.30
27.58
28.00
28.74
28.96
32.70
36.74
38.18
38.38
38.52
39.31
wherein the process comprises crystallizing the crystal form by slow evaporation from dimethoxyether.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a crystal form obtainable by the process of claim 1, and optionally one or more carriers, excipients or diluents.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is for oral, mucosal, parenteral, transdermal or topical administration.

### Claim 13 (depends on 11)

The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is a single unit oral dosage form.

### Claim 14 (depends on 2)

A pharmaceutical composition comprising a crystal form obtainable by the process of claim 2, and optionally one or more carriers, excipients or diluents.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is for oral, mucosal, parenteral, transdermal or topical administration.

### Claim 16 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is a single unit oral dosage form.